Processes for producing cycloalkylcarboxamido-pyridine benzoic acids

ABSTRACT

The present invention relates to a process of providing the 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid in substantially free form (Compound 1).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119 to U.S.provisional patent application Ser. Nos. 61/012,181, filed Dec. 7, 2007,and 61/109,573, filed Oct. 30, 2008, the entire contents of bothapplications are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to processes for the preparation ofcompounds useful for treating a CFTR mediated disease such as cysticfibrosis.

BACKGROUND OF THE INVENTION

CFTR is a cAMP/ATP-mediated anion channel that is expressed in a varietyof cells types, including absorptive and secretory epithelia cells,where it regulates anion flux across the membrane, as well as theactivity of other ion channels and proteins. In epithelia cells, normalfunctioning of CFTR is critical for the maintenance of electrolytetransport throughout the body, including respiratory and digestivetissue. CFTR is composed of approximately 1480 amino acids that encode aprotein made up of a tandem repeat of transmembrane domains, eachcontaining six transmembrane helices and a nucleotide binding domain.The two transmembrane domains are linked by a large, polar, regulatory(R)-domain with multiple phosphorylation sites that regulate channelactivity and cellular trafficking.

The gene encoding CFTR has been identified and sequenced (See Gregory,R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). Adefect in this gene causes mutations in CFTR resulting in cysticfibrosis (“CF”), the most common fatal genetic disease in humans. Cysticfibrosis affects approximately one in every 2,500 infants in the UnitedStates. Within the general United States population, up to 10 millionpeople carry a single copy of the defective gene without apparent illeffects. In contrast, individuals with two copies of the CF associatedgene suffer from the debilitating and fatal effects of CF, includingchronic lung disease.

In patients with cystic fibrosis, mutations in CFTR endogenouslyexpressed in respiratory epithelia leads to reduced apical anionsecretion causing an imbalance in ion and fluid transport. The resultingdecrease in anion transport contributes to enhanced mucus accumulationin the lung and the accompanying microbial infections that ultimatelycause death in CF patients. In addition to respiratory disease, CFpatients typically suffer from gastrointestinal problems and pancreaticinsufficiency that, if left untreated, results in death. In addition,the majority of males with cystic fibrosis are infertile and fertilityis decreased among females with cystic fibrosis. In contrast to thesevere effects of two copies of the CF associated gene, individuals witha single copy of the CF associated gene exhibit increased resistance tocholera and to dehydration resulting from diarrhea—perhaps explainingthe relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease causingmutations in the CF gene have been identified(http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation isa deletion of phenylalanine at position 508 of the CFTR amino acidsequence, and is commonly referred to as ΔF508-CFTR. This mutationoccurs in approximately 70% of the cases of cystic fibrosis and isassociated with a severe disease.

The deletion of residue 508 in ΔF508-CFTR prevents the nascent proteinfrom folding correctly. This results in the inability of the mutantprotein to exit the ER, and traffic to the plasma membrane. As a result,the number of channels present in the membrane is far less than observedin cells expressing wild-type CFTR. In addition to impaired trafficking,the mutation results in defective channel gating. Together, the reducednumber of channels in the membrane and the defective gating lead toreduced anion transport across epithelia leading to defective ion andfluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studieshave shown, however, that the reduced numbers of ΔF508-CFTR in themembrane are functional, albeit less than wild-type CFTR. (Dalemans etal. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk andFoskett (1995), J. Cell. Biochem. 270: 12347-50). In addition toΔF508-CFTR, other disease causing mutations in CFTR that result indefective trafficking, synthesis, and/or channel gating could be up- ordown-regulated to alter anion secretion and modify disease progressionand/or severity.

Although CFTR transports a variety of molecules in addition to anions,it is clear that this role (the transport of anions) represents oneelement in an important mechanism of transporting ions and water acrossthe epithelium. The other elements include the epithelial Na⁺ channel,ENaC, Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and the basolateralmembrane K⁺ channels, that are responsible for the uptake of chlorideinto the cell.

These elements work together to achieve directional transport across theepithelium via their selective expression and localization within thecell. Chloride absorption takes place by the coordinated activity ofENaC and CFTR present on the apical membrane and the Na⁺—K⁺-ATPase pumpand Cl-channels expressed on the basolateral surface of the cell.Secondary active transport of chloride from the luminal side leads tothe accumulation of intracellular chloride, which can then passivelyleave the cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

As discussed above, it is believed that the deletion of residue 508 inΔF508-CFTR prevents the nascent protein from folding correctly,resulting in the inability of this mutant protein to exit the ER, andtraffic to the plasma membrane. As a result, insufficient amounts of themature protein are present at the plasma membrane and chloride transportwithin epithelial tissues is significantly reduced. Infact, thiscellular phenomenon of defective ER processing of ABC transporters bythe ER machinery, has been shown to be the underlying basis not only forCF disease, but for a wide range of other isolated and inheriteddiseases. The two ways that the ER machinery can malfunction is eitherby loss of coupling to ER export of the proteins leading to degradation,or by the ER accumulation of these defective/misfolded proteins [AridorM, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al.,Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al.,Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et al., TIPS, 21,pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198(1999)].

3-(6-(1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid in salt form is disclosed in International PCT Publication WO2007056341 (said publication being incorporated herein by reference inits entirety) as a modulator of CFTR activity and thus useful intreating CFTR-mediated diseases such as cystic fibrosis. There remains,however, a need for economical processes for the preparation of thecycloalkylcarboxamidopyridine benzoic acids described herein.

SUMMARY OF THE INVENTION

As described herein, the present invention provides processes forpreparing CFTR correctors useful in the treatment of cystic fibrosis.Such compounds include3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid (hereinafter “Compound 1”) which has the structure below:

Compound 1 and pharmaceutically acceptable compositions thereof areuseful for treating or lessening the severity of a variety of CFTRmediated diseases. Compound 1 is in a substantially crystalline and saltfree form referred to as Form I as described and characterized herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an X-ray diffraction pattern calculated from a single crystalstructure of Compound 1 in Form I.

FIG. 2 is an actual X-ray powder diffraction pattern of Compound 1 inForm I.

FIG. 3 is an overlay of an X-ray diffraction pattern calculated from asingle crystal of Compound 1 in Form I, and an actual X-ray powderdiffraction pattern of Compound 1 in Form I.

FIG. 4 is a differential scanning calorimetry (DSC) trace of Compound 1in Form I.

FIG. 5 is a conformational picture of Compound 1 in Form I based onsingle crystal X-ray analysis.

FIG. 6 is a conformational picture of Compound 1 in Form I based onsingle crystal X-ray analysis as a dimer formed through the carboxylicacid groups.

FIG. 7 is a conformational picture of Compound 1 in Form I based onsingle crystal X-ray analysis showing that the molecules are stackedupon each other.

FIG. 8 is conformational picture of Compound 1 in Form I based on singlecrystal X-ray analysis showing a different view (down a).

FIG. 9 is an ¹HNMR analysis of Compound 1 in Form I in a 50 mg/mL, 0.5methyl cellulose-polysorbate 80 suspension at T(0).

FIG. 10 is an ¹HNMR analysis of Compound 1 in Form I in a 50 mg/mL, 0.5methyl cellulose-polysorbate 80 suspension stored at room temperaturefor 24 hours.

FIG. 11 is an ¹HNMR analysis of Compound 1.HCl standard.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for preparing Compound 1:

comprising the steps of:

i) providing 2-bromo-3-methylpyridine (compound 2) and3-(t-butoxycarbonyl)phenylboronic acid (compound 3),

ii) cross coupling compound 2 and compound 3 in a biphasic mixturecomprising water, an organic solvent, a base, and a transition metalcatalyst to produce compound 4,

iii) oxidizing compound 4 to produce compound 5,

iv) adding an amine group to the 6 position of the pyridyl moiety toproduce compound 6,

v) reacting compound 6 with compound 7,

in an organic solvent in the presence of a base to produce compound 8,

vi) de-esterifying compound 8 in a biphasic mixture comprising water, anorganic solvent, and an acid to produce compound 9,

vii) slurrying or dissolving compound 9 in an appropriate solvent for aneffective amount of time to produce Compound 1, which is a free form ofcompound 9 and is sometimes referred to as Form I as characterizedherein.

In other embodiments, the process for preparing Compound 1 comprises thestep of:

i) reacting compound 6,

with compound 7,

in an organic solvent in the presence of a base to produce compound 8,

ii) de-esterifying compound 8 in a biphasic mixture comprising water, anorganic solvent, and an acid to produce compound 9,

iii) slurrying or dissolving compound 9 in an appropriate solvent for aneffective amount of time to produce Compound 1.

The present invention also provides a process for preparing a compoundof formula I:

comprising the step of:

ia) reacting a compound of formula 6a:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive;    with a compound of formula 7a:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   m is an integer from 0 to 3 inclusive;-   n is an integer from 1 to 4 inclusive; and-   X is a halo or OH;    in an organic solvent in the presence of a base.

The present invention provides a process for preparing a compound offormula 6a:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive;    comprising the steps of:

ib) providing compound 2a and compound 3a,

wherein,

-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 4 inclusive; and-   p is an integer from 0 to 5 inclusive;

iib) cross coupling compound 2a and compound 3a in a biphasic mixturecomprising water, an organic solvent, a base, and a transition metalcatalyst to produce compound 4a,

wherein, R₁, o, and p are as defined for compounds 2a and 3a above;

iiib) oxidizing compound 4a to produce compound 5a,

wherein, R₁, o, and p are as defined for compounds 2a and 3a above;

ivb) adding an amine group to the 6 position of the pyridyl moiety toproduce compound 6a,

wherein,

R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, orheterocycloalkyl; and

-   R₁, o, and p are as defined for compounds 2a and 3a above.

The present invention also provides a process for preparing a compoundof formula 7a:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   m is an integer from 0 to 3 inclusive;-   n is an integer from 1 to 4 inclusive; and-   X is a halide or OH;    comprising the steps of

ib) reducing Compound 10b:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic; and-   m is an integer from 0 to 3 inclusive,    with a reducing agent to produce Compound 11b:

wherein, ring A, R₁, and m are as defined in Compound 10b above;

iib) reacting Compound 11b with a halogenating agent to produce Compound12b:

wherein, ring A, R₁, and m are as defined in Compound 10b above, and Halis a halide;

iiib) reacting Compound 12b with a cyanide to produce Compound 13b:

wherein, ring A, R₁, and m are as defined in Compound 10b above;

ivb) reacting Compound 13b with a compound of formula 13bb in thepresence of a base:

wherein,

-   Hal is a halide; and-   q is an integer from 0 to 3 inclusive; to produce a compound of    formula 14b:

wherein,

-   r is an integer from 1 to 4 inclusive; and-   ring A, R₁, and m are as defined in Compound 10b above;

vb) sequentially reacting Compound 14b with a hydroxide base and acid toform Compound 15b, which is compound 7a when X═OH:

wherein, r, ring A, R₁, and m are as defined in Compound 14b above; and

vib) reacting Compound 15b with a halogenating agent to form Compound16b, which is compound 7a when X=halide:

wherein,

-   Hal is halide; and-   r, ring A, R₁, and m are as defined in Compound 14b above.

The present invention also provides a process for preparing Compound 1from compound 9 below:

said process comprising the step of slurrying compound 9 in anappropriate solvent and stirring for an effective amount of time toproduce Compound 1.

The present invention also provides a process for preparing Compound 1from compound 9 below:

said process comprising the steps of slurrying compound 9, addingaqueous NaOH, and effecting recrystallization to produce Compound 1.

The present invention also provides a compound of formula 6b:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ and R₂ are independently selected from —R^(J), —OR^(J),    —N(R^(J))₂, —NO₂, halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy,    —C(O)N(R^(J))₂, —NR^(J)C(O)R^(J), —SOW, —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive.

DEFINITIONS

As used herein, the following definitions shall apply unless otherwiseindicated.

The term “CFTR” as used herein means cystic fibrosis transmembraneconductance regulator or a mutation thereof capable of regulatoractivity, including, but not limited to, ΔF508 CFTR and G551D CFTR (see,e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

As used herein “crystalline” refers to compounds or compositions wherethe structural units are arranged in fixed geometric patterns orlattices, so that crystalline solids have rigid long range order. Thestructural units that constitute the crystal structure can be atoms,molecules, or ions. Crystalline solids show definite melting points.

As art-recognized the bidentate ligand (dppf) as in Pd(dppf)Cl₂ standsfor diphenylphosphinoferrocene and as the formula Ph₂PC₅H₄FeC₅H₄PPh₂.

The term “modulating” as used herein means increasing or decreasing,e.g. activity, by a measurable amount.

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below) representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, Figure arepresents possible substitution in any of the positions shown in Figureb.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools, probes inbiological assays, or CFTR correctors with improved therapeutic profile.

In one embodiment, the present invention provides a process forpreparing Compound 1:

In some embodiments, the process for preparing Compound 1 comprises thesteps of:

i) providing 2-bromo-3-methylpyridine (compound 2) and3-(t-butoxycarbonyl)phenylboronic acid (compound 3),

ii) cross coupling compound 2 and compound 3 in a biphasic mixturecomprising water, a first organic solvent, a first base, and atransition metal catalyst to produce compound 4,

iii) oxidizing compound 4 to produce compound 5,

iv) adding an amine group to the 6 position of the pyridyl moiety toproduce compound 6,

v) reacting compound 6 with compound 7,

in a second organic solvent in the presence of a second base to producecompound 8,

vi) de-esterifying compound 8 in a biphasic mixture comprising water, athird organic solvent, and a first acid to produce compound 9,

vii) slurrying or dissolving compound 9 in an appropriate solvent for aneffective amount of time to produce Compound 1.

In some embodiments, the first organic solvent is an aprotic solvent.

In some embodiments, the first organic solvent is selected from1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes,methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone,acetone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide.

In some embodiments, the first organic solvent is selected fromacetonitrile, toluene, benzene, or xylenes. In some embodiments, thefirst organic solvent is toluene.

In other embodiments, the first organic solvent is a protic solvent. Insome embodiments, the first organic solvent is selected from methanol,ethanol, or isopropanol.

In some embodiments, the first base is an inorganic base.

In some embodiments, the first base is selected from potassiumcarbonate, cesium carbonate, potassium phosphate, sodium carbonate,sodium phosphate, sodium hydroxide, potassium hydroxide or lithiumhydroxide.

In some other embodiments, the first base is selected from potassiumcarbonate, cesium carbonate or potassium phosphate. In yet otherembodiments, the first base is selected from potassium carbonate.

In some embodiments, the transition-metal catalyst is a palladium-basedcatalyst.

In some embodiments, the palladium-based catalyst is selected frompalladium(II)acetate, Pd(dppf)Cl₂,tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0). In yet other embodiments, thepalladium-based catalyst is Pd(dppf)Cl₂.

In some embodiments, the cross coupling reaction is run at between about60° C. and about 100° C.

In other embodiments, the cross coupling reaction is run at betweenabout 70° C. and about 90° C. In yet other embodiments, the crosscoupling reaction is run at about 80° C.

In some embodiments, the oxidation reaction is carried out using aperoxide.

In some embodiments, the oxidation reaction is carried out using aperoxide selected from urea-hydrogen peroxide, peracetic acid, methylethyl ketone peroxide, sodium peroxide, hydrogen peroxide, potassiumperoxide, lithium peroxide, barium peroxide, calcium peroxide, strontiumperoxide, magnesium peroxide, zinc peroxide, cadmium peroxide, ormercury peroxide. In some embodiments the oxidation reaction is carriedout using peracetic acid.

In some embodiments, the oxidation reaction is carried out in thepresence of an anhydride.

In some embodiments, the oxidation reaction is carried out in thepresence of an anhydride selected from acetic anhydride, phthalicanhydride, or maleic anhydride. In some embodiments, the oxidationreaction is carried out in the presence of phthalic anhydride.

In some embodiments, the oxidation reaction is run at between about 25°C. and about 65° C.

In some embodiments, the oxidation reaction is run at between about 35°C. and about 55° C. In yet other embodiments, the oxidation reaction isrun at about 45° C.

In some embodiments, the amination reaction is carried out in thepresence of a sulfonyl compound.

In some embodiments, the amination reaction is carried out in thepresence of a sulfonyl compound selected from p-toluenesulfonylchloride, methanesulfonic anhydride, methansulfonyl chloride, orp-toluenesulfonic anhydride. In some embodiments, the amination reactionis carried out in the presence of methanesulfonic anhydride.

In some embodiments, the amination reaction is carried out at ambienttemperatures.

In some embodiments, the amination reagent used in the aminationreaction is an alcohol amine.

In some embodiments, the amination reagent used in the aminationreaction is an alcohol amine selected from methanolamine, ethanolamine,propanolamine, butanolamine, pentanolamine, or hexanolamine. In someembodiments, the amination reagent used in the amination reaction isethanolamine.

In some embodiments, the second organic solvent is an aprotic solvent.

In some embodiments, the second organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the second organic solvent istoluene.

In some embodiments, the second base is an organic base.

In some embodiments, the second base is an organic base selected fromtriethylamine, trimethylamine, methylamine, diethylamine,tripropylamine, ethylmethylamine, diethylmethylamine, or pyridine. Insome embodiments, the second base is triethylamine.

In some embodiments, the reaction between compound 6 and compound 7 iscarried out in the presence of a catalytic amine. In some embodiments,the reaction between compound 6 and compound 7 is carried out in thepresence of a catalytic amount of dimethylaminopyridine.

In some embodiments, the third organic solvent is an aprotic solvent.

In some embodiments, the third organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the third organic solvent isacetonitrile.

In some embodiments, the first acid is an inorganic acid.

In some embodiments, the first acid is an inorganic acid selected fromhydrochloric, sulfuric, nitric, phosphoric, or boric acid. In someembodiments, the first acid is hydrochloric acid.

In some embodiments, the de-esterification reaction is run at betweenabout 20° C. and about 60° C.

In other embodiments, the de-esterification reaction is run at betweenabout 30° C. and about 50° C. In still other embodiments, thede-esterification reaction is run at about 40° C.

In some embodiments, the appropriate solvent is selected from water oran alcohol/water mixture. In some embodiments, the appropriate solventis selected from water or an about 50% methanol/water mixture. In otherembodiments, the appropriate solvent is water.

In some embodiments, the effective amount of time is between about 2 andabout 24 hours.

In some embodiments, the effective amount of time is between about 2 andabout 18 hours. In other embodiments, the effective amount of time isbetween about 2 and about 12 hours. In still other embodiments, theeffective amount of time is between about 2 and about 6 hours.

In other embodiments, the process further comprises the step offiltering the slurry of Compound 1 or concentrating the solution ofCompound 1 to effect recrystallization and filter the recrystallizedCompound 1.

In other embodiments, Compound 1 is further purified byrecrystallization from an organic solvent. Examples of organic solventsinclude, but are not limited to, toluene, cumene, anisole, 1-butanol,isopropyl acetate, butyl acetate, isobutyl acetate, methyl t-butylether, methyl isobutyl ketone, or 1-propanol/water (at various ratios).For example, in one embodiment, Compound 1 is dissolved in 1-butanol atabout 75° C. until it is completely dissolved. Cooling down the solutionto about 10° C. at a rate of about 0.2° C./min yields crystals ofCompound 1 which may be isolated by filtration.

In other embodiments, the process for preparing Compound 1 comprises thestep of:

i) reacting compound 6,

with compound 7,

in a second organic solvent in the presence of a second base to producecompound 8,

ii) de-esterifying compound 8 in a biphasic mixture comprising water, athird organic solvent, and a first acid to produce compound 9,

iii) slurrying or dissolving compound 9 in an appropriate solvent for aneffective amount of time to produce Compound 1.

In some embodiments, the second organic solvent is an aprotic solvent.

In some embodiments, the second organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the second organic solvent istoluene.

In some embodiments, the second base is an organic base.

In some embodiments, the second base is an organic base selected fromtriethylamine, trimethylamine, methylamine, diethylamine,tripropylamine, ethylmethylamine, diethylmethylamine, or pyridine. Insome embodiments, the second base is triethylamine.

In some embodiments, the reaction between compound 6 and compound 7 iscarried out in the presence of a catalytic amine. In some embodiments,the reaction is carried out in the presence of a catalytic amount ofdimethylaminopyridine.

In some embodiments, the third organic solvent is an aprotic solvent.

In some embodiments, the third organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the third organic solvent isacetonitrile.

In some embodiments, the first acid is an inorganic acid.

In some embodiments, the first acid is an inorganic acid selected fromhydrochloric, sulfuric, nitric, phosphoric, or boric acid. In someembodiments, the first acid is hydrochloric acid.

In some embodiments, the de-esterification reaction is run at betweenabout 20° C. and about 60° C.

In other embodiments, the de-esterification reaction is run at betweenabout 30° C. and about 50° C. In still other embodiments, thede-esterification reaction is run at about 40° C.

In some embodiments, the appropriate solvent is selected from water oran alcohol/water mixture. In some embodiments, the appropriate solventis selected from water or an about 50% methanol/water mixture. In otherembodiments, the appropriate solvent is water.

In some embodiments, the effective amount of time is between about 2 andabout 24 hours.

In some embodiments, the effective amount of time is between about 2 andabout 18 hours. In other embodiments, the effective amount of time isbetween about 2 and about 12 hours. In still other embodiments, theeffective amount of time is between about 2 and about 6 hours.

In other embodiments, the process further comprises the step offiltering the slurry of Compound 1 or concentrating the solution ofCompound 1 to effect recrystallization and filter the recrystallizedCompound 1.

In some embodiments, Compound 1 is further purified by recrystallizationfrom an organic solvent. In other embodiments, Compound 1 is furtherpurified by recrystallization from an organic solvent. Examples oforganic solvents include, but are not limited to, toluene, cumene,anisole, 1-butanol, isopropyl acetate, butyl acetate, isobutyl acetate,methyl t-butyl ether, methyl isobutyl ketone, or 1-propanol/water (atvarious ratios). For example, in one embodiment, Compound 1 is dissolvedin 1-butanol at about 75° C. until it is completely dissolved. Coolingdown the solution to about 10° C. at a rate of about 0.2° C./min yieldscrystals of Compound 1 which may be isolated by filtration.

In another embodiment, the present invention provides a process forpreparing a compound of formula 1:

comprising the step of:

ia) reacting a compound of formula 6a:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive;    with a compound of formula 7a:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   m is an integer from 0 to 3 inclusive;-   n is an integer from 1 to 4 inclusive; and-   X is a halo or OH;    in a second organic solvent in the presence of a second base.

In some embodiments, the second organic solvent is an aprotic solvent.

In some embodiments, the second organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the second organic solvent istoluene.

In some embodiments, the second base is an organic base.

In some embodiments, the second base is an organic base selected fromtriethylamine, trimethylamine, methylamine, diethylamine,tripropylamine, ethylmethylamine, diethylmethylamine, or pyridine. Insome embodiments, the second base is triethylamine.

In some embodiments, the reaction of compound 6a with compound 7a iscarried out in the presence of a catalytic amine. In some embodiments,the reaction is carried out in the presence of a catalytic amount ofdimethylaminopyridine.

In some embodiments, when R₁ on the phenyl ring in formula I is anester, the process further comprises de-esterifying the compound in abiphasic mixture comprising water, a third organic solvent, and a firstacid to give an acid salt.

In some embodiments, the third organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the third organic solvent isacetonitrile.

In some embodiments, the first acid is an inorganic acid.

In some embodiments, the third acid is an inorganic acid selected fromhydrochloric, sulfuric, nitric, phosphoric, or boric acid. In someembodiments, the first acid is hydrochloric acid.

In some embodiments, the de-esterification reaction is run at betweenabout 20° C. and about 60° C.

In other embodiments, the de-esterification reaction is run at betweenabout 30° C. and about 50° C. In still other embodiments, thede-esterification reaction is run at about 40° C.

In some embodiments, the acid salt can be converted to the free form,Form I, by slurrying or dissolving the acid salt in an appropriatesolvent for an effective amount of time.

In some embodiments, the appropriate solvent is selected from water oran alcohol/water mixture. In some embodiments, the appropriate solventis selected from water or an about 50% methanol/water mixture. In otherembodiments, the appropriate solvent is water.

In some embodiments, the effective amount of time is between about 2 andabout 24 hours.

In some embodiments, the effective amount of time is between about 2 andabout 18 hours. In other embodiments, the effective amount of time isbetween about 2 and about 12 hours. In still other embodiments, theeffective amount of time is between about 2 and about 6 hours.

In other embodiments, the process further comprises the step offiltering the slurry of the compound of formula I in Form I, orconcentrating the solution of the compound of formula I in Form Itoeffect recrystallization and filtering the recrystallized compound offormula I in Form I.

In other embodiments, Compound 1 is further purified byrecrystallization from an organic solvent. Examples of organic solventsinclude, but are not limited to, toluene, cumene, anisole, or 1-butanol.For example, in one embodiment, Compound 1 is dissolved in 1-butanol atabout 75° C. until it is completely dissolved. Cooling down the solutionto about 10° C. at a rate of about 0.2° C./min yields crystals ofCompound 1 which may be isolated by filtration.

In another embodiment, the present invention provides a process forpreparing a compound of formula 6a:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive;    comprising the steps of:

ib) providing compound 2a and compound 3a,

wherein,

-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 4 inclusive; and-   p is an integer from 0 to 5 inclusive;

iib) cross coupling compound 2a and compound 3a in a biphasic mixturecomprising water, a first organic solvent, a first base, and atransition metal catalyst to produce compound 4a,

wherein, R₁, o, and p are as defined for compounds 2a and 3a above;

iiib) oxidizing compound 4a to produce compound 5a,

wherein, R₁, o, and p are as defined for compounds 2a and 3a above;

ivb) adding an amine group to the 6 position of the pyridyl moiety toproduce compound 6a,

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl; and-   R₁, o, and p are as defined for compounds 2a and 3a above.

In some embodiments, the first organic solvent is an aprotic solvent.

In some embodiments, the first organic solvent is selected from1,2-dimethoxyethane, dioxane, acetonitrile, toluene, benzene, xylenes,methyl t-butyl ether, methyl ethyl ketone, methyl isobutyl ketone,acetone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide.

In some embodiments, the first organic solvent is selected fromacetonitrile, toluene, benzene, or xylenes. In some embodiments, thefirst organic solvent is toluene.

In other embodiments, the first organic solvent is a protic solvent. Insome embodiments, the first organic solvent is selected from methanol,ethanol, or isopropanol.

In some embodiments, the first base is an inorganic base.

In some embodiments, the first base is selected from potassiumcarbonate, cesium carbonate, potassium phosphate, sodium carbonate,sodium phosphate, sodium hydroxide, potassium hydroxide or lithiumhydroxide.

In some other embodiments, the first base is selected from potassiumcarbonate, cesium carbonate or potassium phosphate. In yet otherembodiments, the first base is potassium carbonate.

In some embodiments, the transition-metal catalyst is a palladium-basedcatalyst.

In some embodiments, the palladium-based catalyst is selected frompalladium(II)acetate, Pd(dppf)Cl₂,tetrakis(triphenylphosphine)palladium(0) ortris(dibenzylideneacetone)dipalladium(0). In yet other embodiments, thepalladium-based catalyst is Pd(dppf)Cl₂.

In some embodiments, the cross coupling reaction is run at between about60° C. and about 100° C.

In other embodiments, the cross coupling reaction is run at betweenabout 70° C. and about 90° C. In yet other embodiments, the crosscoupling reaction is run at about 80° C.

In some embodiments, the oxidation reaction is carried out using aperoxide.

In some embodiments, the oxidation reaction is carried out using aperoxide selected from urea-hydrogen peroxide, peracetic acid, methylethyl ketone peroxide, sodium peroxide, hydrogen peroxide, potassiumperoxide, lithium peroxide, barium peroxide, calcium peroxide, strontiumperoxide, magnesium peroxide, zinc peroxide, cadmium peroxide, ormercury peroxide. In some embodiments the oxidation reaction is carriedout using peracetic acid.

In some embodiments, the oxidation reaction is carried out in thepresence of an anhydride.

In some embodiments, the oxidation reaction is carried out in thepresence of an anhydride selected from acetic anhydride, phthalicanhydride, or maleic anhydride. In some embodiments, the oxidationreaction is carried out in the presence of phthalic anhydride.

In some embodiments, the oxidation reaction is run at between about 25°C. and about 65° C.

In some embodiments, the oxidation reaction is run at between about 35°C. and about 55° C. In yet other embodiments, the oxidation reaction isrun at about 45° C.

In some embodiments, the amination reaction is carried out in thepresence of a sulfonyl compound.

In some embodiments, the amination reaction is carried out in thepresence of a sulfonyl compound selected from p-toluenesulfonylchloride, methanesulfonic anhydride, methansulfonyl chloride, orp-toluenesulfonic anhydride. In some embodiments, the amination reactionis carried out in the presence of methanesulfonic anhydride.

In some embodiments, the amination reaction is carried out at ambienttemperatures.

In some embodiments, the amination reagent used in the aminationreaction is an alcohol amine.

In some embodiments, the amination reagent used in the aminationreaction is an alcohol amine selected from methanolamine, ethanolamine,propanolamine, butanolamine, pentanolamine, or hexanolamine. In someembodiments, the amination reagent used in the amination reaction isethanolamine.

The present invention also provides a process for preparing a compoundof formula 7a:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   m is an integer from 0 to 3 inclusive;-   n is an integer from 1 to 4 inclusive; and-   X is a halide or OH;    comprising the steps of

ic) reducing Compound 10a in a fourth organic solvent:

wherein,

-   A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring;-   R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂,    halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂,    —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic; and-   m is an integer from 0 to 3 inclusive,    with a reducing agent to produce Compound 11a:

wherein, ring A, R₁, and m are as defined in Compound 10a above;

iic) reacting Compound 11a with a first halogenating agent in a fifthorganic solvent to produce Compound 12a:

wherein, ring A, R₁, and m are as defined in Compound 10a above, and Halis a halide;

iiic) reacting Compound 12a with a cyanide to produce Compound 13a:

wherein, ring A, R₁, and m are as defined in Compound 10a above;

ivc) reacting Compound 13a with a compound of formula 13aa in thepresence of a third base:

wherein,

-   Hal is a halide; and-   q is an integer from 0 to 3 inclusive; to produce a compound of    formula 14a:

wherein,

-   r is an integer from 1 to 4 inclusive; and-   ring A, R₁, and m are as defined in Compound 10a above;

vc) sequentially reacting Compound 14a with a hydroxide base and secondacid to form Compound 15a, which is compound 7a when X═OH:

wherein, r, ring A, R₁, and m are as defined in Compound 14a above; and

vic) reacting Compound 15a with a second halogenating agent in a sixthorganic solvent to form Compound 16a, which is compound 7a whenX=halide:

wherein,

-   Hal is halide; and-   r, ring A, R₁, and m are as defined in Compound 14a above.

In some embodiments, the fourth organic solvent is an aprotic solvent.

In some embodiments, the fourth organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methylisobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide.

In some embodiments, the fourth organic solvent is selected fromacetonitrile, toluene, benzene, or xylenes. In some embodiments, thefourth organic solvent is toluene.

In some embodiments, the reducing agent is a hydride.

In some embodiments, the reducing agent is sodium hydride, lithiumaluminum hydride, sodium borohydride, or sodiumbis(2-methoxyethoxy)aluminum hydride. In some embodiments, the reducingagent is sodium bis(2-methoxyethoxy)aluminum hydride.

In some embodiments, the reducing reaction is run at between about 5° C.and about 50° C. In other embodiments, the reducing reaction is run atbetween about 15° C. and about 40° C.

In some embodiments, the fifth organic solvent is an aprotic solvent.

In some embodiments, the fifth organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methylisobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide.

In some embodiments, the fifth organic solvent is selected fromacetonitrile, toluene, methyl t-butyl ether, benzene, or xylenes. Insome embodiments, the fifth organic solvent is methyl t-butyl ether.

In some embodiments, the first halogenating agent is a thionyl halide.In other embodiments, the first halogenating agent is thionyl chloride.

In some embodiments, the reaction between Compound 11a and the firsthalogenating agent is run at between about 10° C. and about 35° C. Inother embodiments, the halogenating reaction is run at between about 15°C. and about 30° C.

In some embodiments the cyanide is an alkali metal cyanide. In otherembodiments, the cyanide is sodium cyanide.

In some embodiments, Compound 19 is dissolved in an organic solvent andadded to a slurry of an alkali metal cyanide. In other embodiments, theorganic solvent is DMSO.

In some embodiments, reaction of Compound 12a with a cyanide is run atbetween about 10° C. and about 60° C. In other embodiments, the reactionis run at between about 20° C. and about 50° C. In other embodiments,the reaction is run at between about 30° C. and about 40° C.

In some embodiments, the third base in step ivc) is an inorganic base.

In some embodiments, the third base is selected from potassiumcarbonate, cesium carbonate, potassium phosphate, sodium carbonate,sodium phosphate, sodium hydroxide, potassium hydroxide or lithiumhydroxide.

In some embodiments, the third base is sodium hydroxide or potassiumhydroxide. In some embodiments, the third base is potassium hydroxide.

In some embodiments, Compound 13aa is selected from dichloroethane,dichloropropane, dichlorobutane, dichloropentane, dibromoethane,dibromopropane, dibromobutane, dibromopentane, 1-bromo-2-chloroethane,1-bromo-3-chloropropane, 1-bromo-4-chlorobutane, or1-bromo-5-chloropentane.

In some embodiments, Compound 13aa is 1-bromo-2-chloroethane.

In some embodiments the reaction of Compound 13a with a compound offormula 13aa is run at between about 0° C. and about 90° C. In someembodiments the reaction is run at between about 60° C. and about 80° C.In some embodiments the reaction is run at about 70° C.

In some embodiments, the hydroxide base is sodium hydroxide, lithiumhydroxide, or potassium hydroxide. In other embodiments, the hydroxidebase is sodium hydroxide.

In some embodiments the second acid is an inorganic acid. In someembodiments, the second acid is selected from hydrochloric, sulfuric,nitric, phosphoric, or boric acid. In some embodiments, the second acidis hydrochloric acid.

In some embodiments, the sequential reaction of Compound 14a withhydroxide base and second acid is run at between about 70° C. and about90° C. In some embodiments, the reaction is run at about 80° C.

In some embodiments, treating Compound 14a with a hydroxid base is donein the presence of a cosolvent. In other embodiments, the cosolvent isan alcohol. In other embodiments, the alcohol is ethanol.

In some embodiments, after treating Compound 14a with a hydroxide base,it is isolated before treatment with a second acid. In otherembodiments, it is isolated as a different base than what was used tohydrolyze Compound 14a. In other embodiments, the different base used iscyclohexylamine to form the cyclohexylammonium salt.

In some embodiments, the sixth organic solvent is an aprotic solvent.

In some embodiments, the sixth organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methyl ethyl ketone, methylisobutyl ketone, acetone, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, or dimethylsulfoxide.

In some embodiments, the sixth organic solvent is selected fromacetonitrile, toluene, benzene, or xylenes. In some embodiments, thesixth organic solvent is toluene.

In some embodiments, the second halogenating agent is a thionyl halide.In some embodiments the second halogenating agent is thionyl chloride.

In some embodiments, the reaction of Compound 15a with a secondhalogenating agent is run at between about 40° C. and about 80° C. Insome embodiments, the reaction is run at between about 50° C. and about70° C. In some embodiments, the reaction is run at about 70° C.

The present invention also provides a process for preparing Compound 1from compound 9 below:

said process comprising the step of slurrying compound 9 in anappropriate solvent and stirring for an effective amount of time toproduce Compound 1.

The present invention also provides a process for preparing Compound 1from compound 9 below:

said process comprising the steps of slurrying compound 9, addingaqueous NaOH, and effecting recrystallization to produce Compound 1.

In some embodiments, recrystallization is achieved by addingconcentrated HCl.

In some embodiments, the appropriate solvent is water or an about 50%methanol/water mixture. In some embodiments, the appropriate solvent iswater.

In some embodiments, the effective amount of time is between about 2hours and about 24 hours. In some embodiments, the effective amount oftime is between about 2 hours and about 18 hours. In some embodiments,the effective amount of time is between about 2 hours and about 12hours. In some embodiments, the effective amount of time is betweenabout 2 hours and about 6 hours.

In some embodiments, the process further comprises the step of filteringthe slurry of Compound 1.

In other embodiments, compound 9 is produced from compound 8 below:

said process comprising the step of de-esterifying compound 8 in abiphasic mixture comprising water, a third organic solvent, and a firstacid to produce compound 9.

In some embodiments, the third organic solvent is an aprotic solvent. Insome embodiments, the third organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the third organic solvent isacetonitrile.

In some embodiments, the first acid is an inorganic acid. In someembodiments, the first acid is selected from hydrochloric, sulfuric,nitric, phosphoric, or boric acid. In some embodiments, the first acidis hydrochloric acid.

In some embodiments, the de-esterification reaction is run at betweenabout 20° C. and about 60° C. In some embodiments, the de-esterificationreaction reaction is run at between about 30° C. and about 50° C. Insome embodiments, the de-esterification reaction is run at about 40° C.

In some embodiments, compound 8 is prepared from compound 6 and compound7 below:

said process comprising the step reacting compound 6 with compound 7 ina second organic solvent in the presence of a second base to producecompound 8,

In some embodiments, the second organic solvent is an aprotic solvent.In some embodiments, the second organic solvent is an aprotic solventselected from 1,2-dimethoxyethane, dioxane, acetonitrile, toluene,benzene, xylenes, methyl t-butyl ether, methylene chloride, chloroform,methyl ethyl ketone, methyl isobutyl ketone, acetone,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, ordimethylsulfoxide. In some embodiments, the second organic solvent istoluene.

In some embodiments, the second base is an organic base. In someembodiments, the second base is selected from triethylamine,trimethylamine, methylamine, diethylamine, tripropylamine,ethylmethylamine, diethylmethylamine, or pyridine. In some embodiments,the second base is triethylamine.

In some embodiments, the process is carried out in the presence of acatalytic amine. In some embodiments, the catalytic amine isdimethylaminopyridine.

In some embodiments, compound 6 is prepared from compound 4 below:

said process comprising the steps of:

-   -   oxidizing compound 4 to produce compound 5

-   -   aminating compound 5 to add an amine group to the 6-position of        the pyridyl moiety on compound 5 to produce compound 6,

In some embodiments, the oxidation reaction is carried out using aperoxide. In some embodiments, the peroxide is selected fromurea-hydrogen peroxide, peracetic acid, methyl ethyl ketone peroxide,sodium peroxide, hydrogen peroxide, potassium peroxide, lithiumperoxide, barium peroxide, calcium peroxide, strontium peroxide,magnesium peroxide, zinc peroxide, cadmium peroxide, or mercuryperoxide. In some embodiments, the peroxide is peracetic acid.

In some embodiments, the oxidation reaction is carried out in thepresence of an anhydride. In some embodiments, the anhydride is selectedfrom acetic anhydride, phthalic anhydride, or maleic anhydride. In someembodiments, the anhydride is phthalic anhydride.

In some embodiments, the oxidation reaction is run at between about 25°C. and about 65° C. In some embodiments, the oxidation reaction is runat between about 35° C. and about 55° C. In some embodiments, theoxidation reaction is run at about 45° C.

In some embodiments, the amination reaction is carried out in thepresence of a sulfonyl compound. In some embodiments, the sulfonylcompound is selected from p-toluenesulfonyl chloride, methanesulfonicanhydride, methansulfonyl chloride, or p-toluenesulfonic anhydride. Insome embodiments, the sulfonyl compound is methanesulfonic anhydride.

In some embodiments, the amination reaction is carried out at ambienttemperature.

In some embodiments, the aminating reagent used in the aminationreaction is an alcohol amine. In some embodiments, the alcohol amine isselected from methanolamine, ethanolamine, propanolamine, butanolamine,pentanolamine, or hexanolamine. In some embodiments, the alcohol amineis ethanolamine.

The present invention also provides a compound of formula 6b:

wherein,

-   R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or    heterocycloalkyl;-   R₁ and R₂ are independently selected from —R^(J), —OR^(J),    —N(R^(J))₂, —NO₂, halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy,    —C(O)N(R^(J))₂, —NR^(J)C(O)R^(J), —SOW, —SO₂R^(J), —SO₂N(R^(J))₂,    —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂,    —COCOR^(J);-   R^(J) is hydrogen or C₁₋₆ aliphatic;-   o is an integer from 0 to 3 inclusive; and-   p is an integer from 0 to 5 inclusive.

In some embodiments, the present invention relates to a compound offormula 6b and the attendant definitions wherein R is H.

In some embodiments, the present invention relates to a compound offormula 6b and the attendant definitions wherein R₁ is C₁₋₆ aliphaticand o is 1.

In some embodiments, the present invention relates to a compound offormula 6b and the attendant definitions wherein R₁ is methyl and o is1.

In some embodiments, the present invention relates to a compound offormula 6b and the attendant definitions wherein R₂ is —CO₂R^(J) and pis 1.

In some embodiments, the present invention relates to a compound offormula 6b and the attendant definitions wherein R₂ is —CO₂R^(J), R^(J)is C₁₋₆ aliphatic, and p is 1.

In some embodiments, the present invention relates to the compound

In some embodiments, Compound 1 may contain a radioactive isotope. Insome embodiments, Compound 1 may contain a ¹⁴C atom. In someembodiments, the amide carbonyl carbon of Compound 1 is a ¹⁴C atom.

Methods of Preparing Compound 1.

Compound 1 is a free form of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid and, in one embodiment, is prepared from dispersing or dissolving asalt form, such as HCl, of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid in an appropriate solvent for an effective amount of time. Inanother embodiment, Form I is formed directly from3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoateand an appropriate acid, such as formic acid. In one embodiment, the HClsalt form of3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid is the starting point and in one embodiment can be prepared bycoupling an acid chloride moiety with an amine moiety according toSchemes 1-3.

Scheme 1. Synthesis of the Acid Chloride Moiety

In Scheme 1, carboxylic acid 17 is reduced with a reducing agent in asuitable solvent (e.g. toluene) to produce alcohol 18. Treatment ofCompound 18 with a chlorinating agent in a suitable solvent (e.g.methyl-t-butyl ether (MTBE)) produces Compound 19. A cyanide groupdisplaces the chloride to yield compound 20. Reaction of compound 20with a base and alkyl dihalide (e.g. 1-bromo-2-chloroethane) yields thespirocycloalkane compound 21. Hydrolization of the cyanide group givesthe carboxylic acid 22 which is chlorinated to yield the acid halide 7.

In one embodiment, Compound 17 is commercially available. In oneembodiment, the reducing agent is sodium bis(2-methoxyethoxy)aluminumhydride [or NaAlH₂(OCH₂CH₂OCH₃)₂], 65 wgt % solution in toluene, whichis sold under the name Vitride® by Aldrich Chemicals.

In one embodiment, the chlorinating agent that converts Compound 18 toCompound 19 is thionyl chloride. In another embodiment, the thionylchloride is added to Compound 18 while maintaining the temperature ofthe reaction mixture at 15° C. to 25° C. and then stirring for anadditional hour continues at 30° C.

In one embodiment, the cyanide group of compound 20 results fromreacting Compound 19 with sodium cyanide in a suitable solvent (e.g.DMSO). In another embodiment, the temperature of the reaction mixture ismaintained at 30° C. to 40° C. while the sodium cyanide is being added.

In one embodiment, compound 20 is reacted with potassium hydroxide andan alkyl dihalide to yield the spirocyclic compound 21 in a suitablesolvent (e.g. water). Although, a spirocyclic propane ring is depictedin Scheme 1, the process is easily adaptable to other spirocyclic ringsby choosing the appropriate alkyl dihalide. For example, a spirocylicbutane ring can be produced by reacting compound 20 with, for example,1-bromo-3-chloropropane. It has been found that a mixed bromo and chlorodihalide works best on an economic scale as it is believed that thethermodynamics of the reaction are more favorable.

In one embodiment, compound 21 is hydrolized to the carboxylic acidcompound 22 in the presence of water and a base (e.g. sodium hydroxide)in a suitable solvent (e.g. ethanol). Subsequent treatment with an acidsuch as hydrochloric acid yields compound 22. In another embodiment,compound 22 is worked up by reacting it with dicyclohexylamine (DCHA) togive the DCHA salt which is taken up in a suitable solvent (e.g. MTBE)and stirred with citric acid until the solids are dissolved. The MTBElayer is then washed with water and brine and a solvent swap withheptane followed by filtration gives compound 22.

In one embodiment, chlorination of compound 22 is carried out in asuitable solvent (e.g. toluene) with thionyl chloride to yield compound7. In one embodiment, this step directly proceeds the coupling betweencompound 7 and compound 6 and is carried out in the same reactionvessel.

There are several non-limiting advantages to forming compound 7according to Scheme 1 and the embodiments described above and elsewherein the application. These advantages are apparent even more so whenmanufacturing compound 7 on an economic scale and include the following.Use of Vitride® over other reducing agents, such as lithium aluminumhydride, to reduce Compound 17 to Compound 18 allows controlled(manageable exothermic reaction and gas evolution) and safe addition ofthe reducing agent. Use of DMAP as a catalyst in the halogenatingreaction of Compound 18 to Compound 19 as opposed to certain other basessuch as DMF avoids formation of dimethylcarbamoyl chloride, a knowncarcinogen. Adding a solution of Compound 19 in an organic solvent suchas DMSO to a slurry of the cyanide in an organic solvent such as DMSOcontrols the temperature of the exothermic reaction and minimizes thehandling of the cyanide. Using ethanol as the cosolvent in hydrolyzingcompound 21 to compound 22 results in a homogeneous reaction mixturemaking sampling and monitoring the reaction easier. Purification ofcompound 21 as the dicyclohexylammonium salt after the initialhydrolization eliminates chromatography of any of the intermediates.

Scheme 2. Synthesis of the Amine Moiety

2-Bromo-3-methylpyridine (compound 2) is reacted with3-(t-butoxycarbonyl)-phenylboronic acid (compound 3) in a suitablesolvent (e.g. toluene) to yield the ester compound 4. The couplingreaction is catalyzed by a transition metal catalyst such as a palladiumcatalyst. Oxidation of compound 4 with a peroxide in a suitable solvent(e.g. a ethyl acetate-water mixture) yields compound 5. Amination ofcompound 5 with an aminating agent (e.g. an alcohol amine) yieldscompound 6.

In one embodiment, the palladium catalyst is Pd(dppf)Cl₂ which comprisesa bidentate ferrocene ligand. In another embodiment, the catalyst isused only at 0.025 to 0.005 equivalents to compound 2. In anotherembodiment, the catalyst is used only at 0.020 to 0.010 equivalents tocompound 2. In another embodiment, the catalyst is used only at 0.015equivalents to compound 2.

In one embodiment, oxidation of compound 4 is carried out withurea-hydrogen peroxide or peracetic acid. Peracetic acid is preferred asit is more economically favorable to obtain and easier to isolate anddispose afterwards. In one embodiment, an anhydride is addedportion-wise to the reaction mixture to maintain the temperature in thereaction vessel below 45° C. In one embodiment, the anhydride isphthalic anhydride and it is added in solid form. After completion ofthe anhydride addition, the mixture is heated to 45° C. and stirred forfour hours before isolating compound 5.

In one embodiment, an amine group is added to compound 5 to yieldcompound 6 in a suitable solvent (e.g. pyridine-acetonitrile mixture).In one embodiment, amination occurs after compound 5 is first reactedwith a sulfonic anhydride. In one embodiment, the sulfonic anhydride ismethanesulfonic anhydride dissolved in acetonitrile and added over thecourse of 50 minutes to compound 5 dissolved in pyridine. In anotherembodiment, the temperature is maintained below 75° C. during addition.In another embodiment, the amination agent is ethanolamine. In anotherembodiment, the amount of ethanolamine is 10 equivalents relative tocompound 5.

There are several non-limiting advantages to forming compound 6according to Scheme 2 and the embodiments described above and elsewherein the application. These advantages are apparent even more so whenmanufacturing compound 6 on an economic scale and include the following.Increasing the concentration of potassium carbonate in the couplingreaction of compounds 2 and 3 to form compound 4 reduces the level ofboronic acid homo-coupling. The level of boronic acid homo-coupling isalso reduced by adding the transition metal catalyst last to thereaction mixture after heating under N₂. Extracting compound 4 withaqueous MsOH eliminates the need for chromatographic purification. Usingperacetic acid as the oxidizing agent when converting compound 4 tocompound 5 is more economical than other oxidizing agents and results inmore manageable by-products. Use of Ms₂O instead of other similarreagents, such as p-toluenesulfonyl chloride, in converting compound 5to compound 6 eliminates formation of chloro impurities. Addition ofwater at the completion of the reaction crystallizes compound 6 directlyfrom the reaction mixture improving yield and facilitating isolation.

Scheme 3. Formation of an acid salt of3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid

An acid-base reaction between compound 7 and compound 6 in a suitablesolvent (e.g. toluene) yields the ester compound 8. De-esterification ofcompound 8 with an acid (hydrochloric acid shown) yields compound 9which is the precursor to Compound 1.

In one embodiment, the acid chloride compound 7 is prepared fromcompound 22 as depicted in Scheme 1 in the same reaction vessel and isnot isolated. In another embodiment, the acid-based reaction is carriedout in the presence of a base such as triethylamine (TEA) and acatalytic amount of a second base such as dimethylaminopyridine (DMAP).In one embodiment, the amount of TEA is 3 equivalents relative tocompound 6. In another embodiment, the amount of DMAP is 0.02equivalents relative to compound 6. In one embodiment, after a reactiontime of two hours, water is added to the mixture and stirred for anadditional 30 minutes. The organic phase is separated and compound 9 isisolated by adding a suitable solvent (e.g. acetonitrile) and distillingoff the reaction solvent (e.g. t). Compound 9 is collected byfiltration.

Using compound 9, for example, as a starting point, Compound 1 can beformed in high yields by dispersing or dissolving compound 9 in anappropriate solvent for an effective amount of time. Other salt forms of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid may be used such as, for example, other mineral or organic acidforms. The other salt forms result from hydrolysis of the t-butyl esterwith the corresponding acid. Other acids/salt forms include nitric,sulfuric, phosphoric, boric, acetic, benzoic, malonic, and the like.Compound 9 may or may not be soluble depending upon the solvent used,but lack of solubility does not hinder formation of Compound 1. Forexample, in one embodiment, the appropriate solvent may be water or analcohol/water mixture such as an about 50% methanol/water mixture, eventhough compound 9 is only sparingly soluble in water. In one embodiment,the appropriate solvent is water.

The effective amount of time for formation of Compound 1 from thecompound 9 can be any time between 2 to 24 hours or greater. Generally,greater than 24 hours is not needed to obtain high yields (˜98%), butcertain solvents may require greater amounts of time. It is alsorecognized that the amount of time needed is inversely proportional tothe temperature. That is, the higher the temperature the less timeneeded to affect dissociation of HCl to form Compound 1. When thesolvent is water, stirring the dispersion for approximately 24 hours atroom temperature gives Compound 1 in an approximately 98% yield. If asolution of the compound 9 is desired for process purposes, an elevatedtemperature and organic solvent may be used. After stirring the solutionfor an effective amount of time at the elevated temperature,recrystallization upon cooling yields substantially pure forms ofCompound 1. In one embodiment, substantially pure refers to greater than90% purity. In another embodiment, substantially pure refers to greaterthan 95% purity. In another embodiment, substantially pure refers togreater than 98% purity. In another embodiment, substantially purerefers to greater than 99% purity. The temperature selected depends inpart on the solvent used and is well within the capabilities of someoneof ordinary skill in the art to determine. In one embodiment, thetemperature is between room temperature and 80° C. In anotherembodiment, the temperature is between room temperature and 40° C. Inanother embodiment, the temperature is between 40° C. and 60° C. Inanother embodiment, the temperature is between 60° C. and 80° C.

In some embodiments, Compound 1 may be further purified byrecrystallization from an organic solvent. Examples of organic solventsinclude, but are not limited to, toluene, cumene, anisole, 1-butanol,isopropylacetate, butyl acetate, isobutyl acetate, methyl t-butyl ether,methyl isobutyl ketone, or 1-propanol/water (at various ratios).Temperature may be used as described above. For example, in oneembodiment, Compound 1 is dissolved in 1-butanol at 75° C. until it iscompletely dissolved. Cooling down the solution to 10° C. at a rate of0.2° C./min yields crystals of Compound 1 which may be isolated byfiltration.

There are several non-limiting advantages to forming compound 9according to Scheme 3 and the embodiments described above and elsewherein the application. These advantages are apparent even more so whenmanufacturing compound 9 on an economic scale and include the following.Crystallizing compound 8 after reacting compound 7 with compound 6eliminates chromatographic purification. Direct crystallization ofcompound 9 after treating compound 8 with an acid versus deprotectionwith another acid, such as trifluoroacetic acid, concentration, andexchange with the desired acid, such as HCl, eliminates steps andimproves yields.

In some embodiments, Compound 1 may comprise a radioactive isotope. Insome embodiments, the radioactive isotope is ¹⁴C. In some embodiments,the amide carbonyl carbon of Compound 1 is ¹⁴C. The ¹⁴C is introduced atthis position by reacting compound 19 with a radiolabeled cyanide asdepicted in Scheme 4.

Scheme 4. Introduction of a Radioactive Isotope into Compound 1

In one embodiment, the radiolabeled cyanide group of compound 23 resultsfrom reacting Compound 19 with radiolabeled sodium cyanide in a suitablesolvent (e.g. DMSO). In another embodiment, the temperature of thereaction mixture is maintained at 30° C. to 40° C. while the sodiumcyanide is being added. Compound 23 may then be further reactedaccording to Schemes 1-3 to produce radiolabeled Compound 1.

Characterization of Compound 1

Compound 1 exists as the substantially free form of3-(6(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid, Form I, as characterized herein by X-ray powder diffraction,differential scanning calorimetry (DSC), thermogravimetric analysis(TGA), and ¹HNMR spectroscopy.

In one embodiment, Compound 1 is characterized by one or more peaks at15.2 to 15.6 degrees, 16.1 to 16.5 degrees, and 14.3 to 14.7 degrees inan X-ray powder diffraction obtained using Cu K alpha radiation. Inanother embodiment, Compound 1 is characterized by one or more peaks at15.4, 16.3, and 14.5 degrees. In another embodiment, Compound 1 isfurther characterized by a peak at 14.6 to 15.0 degrees. In anotherembodiment, Compound 1 is further characterized by a peak at 14.8degrees. In another embodiment, Compound 1 is further characterized by apeak at 17.6 to 18.0 degrees. In another embodiment, Compound 1 isfurther characterized by a peak at 17.8 degrees. In another embodiment,Compound 1 is further characterized by a peak at 16.4 to 16.8 degrees.In another embodiment, Compound 1 is further characterized by a peak at16.4 to 16.8 degrees. In another embodiment, Compound 1 is furthercharacterized by a peak at 16.6 degrees. In another embodiment, Compound1 is further characterized by a peak at 7.6 to 8.0 degrees. In anotherembodiment, Compound 1 is further characterized by a peak at 7.8degrees. In another embodiment, Compound 1 is further characterized by apeak at 25.8 to 26.2 degrees. In another embodiment, Compound 1 isfurther characterized by a peak at 26.0 degrees. In another embodiment,Compound 1 is further characterized by a peak at 21.4 to 21.8 degrees.In another embodiment, Compound 1 is further characterized by a peak at21.6 degrees. In another embodiment, Compound 1 is further characterizedby a peak at 23.1 to 23.5 degrees. In another embodiment, Compound 1 isfurther characterized by a peak at 23.3 degrees.

In some embodiments, Compound 1 is characterized by a diffractionpattern substantially similar to that of FIG. 1.

In some embodiments, Compound 1 is characterized by a diffractionpattern substantially similar to that of FIG. 2.

In another embodiment, Compound 1 has a monoclinic crystal system, aP2₁/n space group, and the following unit cell dimensions: a=4.9626 (7)Å; b=12.2994 (18) Å; c=33.075 (4) Å; α=90°; β=93.938 (9)°; and γ=90°.

In another embodiment, Compound 1 is characterized by the DSC traceshown in FIG. 4.

In another embodiment, Compound 1 is characterized by the ¹HNMR spectraof Compound 1 shown in FIGS. 8-10.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Methods & Materials

Differential Scanning Calorimetry (DSC)

The Differential scanning calorimetry (DSC) data of Compound 1 werecollected using a DSC Q100 V9.6 Build 290 (TA Instruments, New Castle,Del.). Temperature was calibrated with indium and heat capacity wascalibrated with sapphire. Samples of 3-6 mg were weighed into aluminumpans that were crimped using lids with 1 pin hole. The samples werescanned from 25° C. to 350° C. at a heating rate of 1.0° C./min and witha nitrogen gas purge of 50 ml/min. Data were collected by ThermalAdvantage Q Series™ version 2.2.0.248 software and analyzed by UniversalAnalysis software version 4.1D (TA Instruments, New Castle, Del.). Thereported numbers represent single analyses.

XRPD (X-ray Powder Diffraction)

The X-Ray diffraction (XRD) data of Form 1 were collected on a Bruker D8DISCOVER powder diffractometer with HI-STAR 2-dimensional detector and aflat graphite monochromator. Cu sealed tube with Kα radiation was usedat 40 kV, 35 mA. The samples were placed on zero-background siliconwafers at 25° C. For each sample, two data frames were collected at 120seconds each at 2 different θ₂ angles: 8° and 26°. The data wereintegrated with GADDS software and merged with DIFFRACT^(plus)EVAsoftware. Uncertainties for the reported peak positions are ±0.2degrees.

Vitride® (sodium bis(2-methoxyethoxy)aluminum hydride [orNaAlH₂(OCH₂CH₂OCH₃)₂], 65 wgt % solution in toluene) was purchased fromAldrich Chemicals.

2,2-Difluoro-1,3-benzodioxole-5-carboxylic acid was purchased fromSaltigo (an affiliate of the Lanxess Corporation).

Anywhere in the present application where a name of a compound may notcorrectly describe the structure of the compound, the structuresupersedes the name and governs.

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid.HCl Acid Chloride Moiety Synthesis of(2,2-difluoro-1,3-benzodioxol-5-yl)-methanol (Compound 18)

Commercially available 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid(1.0 eq) is slurried in toluene (10 vol). Vitride® (2 eq) is added viaaddition funnel at a rate to maintain the temperature at 15-25° C. Atthe end of addition the temperature is increased to 40° C. for 2 h then10% (w/w) aq. NaOH (4.0 eq) is carefully added via addition funnelmaintaining the temperature at 40-50° C. After stirring for anadditional 30 minutes, the layers are allowed to separate at 40° C. Theorganic phase is cooled to 20° C. then washed with water (2×1.5 vol),dried (Na₂SO₄), filtered, and concentrated to afford crude Compound 18that is used directly in the next step.

Synthesis of 5-chloromethyl-2,2-difluoro-1,3-benzodioxole (Compound 19)

Compound 18 (1.0 eq) is dissolved in MTBE (5 vol). A catalytic amount ofDMAP (1 mol %) is added and SOCl₂ (1.2 eq) is added via addition funnel.The SOCl₂ is added at a rate to maintain the temperature in the reactorat 15-25° C. The temperature is increased to 30° C. for 1 hour thencooled to 20° C. then water (4 vol) is added via addition funnelmaintaining the temperature at less than 30° C. After stirring for anadditional 30 minutes, the layers are allowed to separate. The organiclayer is stirred and 10% (w/v) aq. NaOH (4.4 vol) is added. Afterstirring for 15 to 20 minutes, the layers are allowed to separate. Theorganic phase is then dried (Na₂SO₄), filtered, and concentrated toafford crude Compound 19 that is used directly in the next step.

Synthesis of (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (compound20)

A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurryof NaCN (1.4 eq) in DMSO (3 vol) maintaining the temperature between30-40° C. The mixture is stirred for 1 hour then water (6 vol) is addedfollowed by MTBE (4 vol). After stirring for 30 min, the layers areseparated. The aqueous layer is extracted with MTBE (1.8 vol). Thecombined organic layers are washed with water (1.8 vol), dried (Na₂SO₄),filtered, and concentrated to afford crude compound 20 (95%) that isused directly in the next step.

Synthesis of(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile (compound21)

A mixture of compound 20 (1.0 eq), 50 wt % aqueous KOH (5.0 eq)1-bromo-2-chloroethane (1.5 eq), and Oct₄NBr (0.02 eq) is heated at 70°C. for 1 h. The reaction mixture is cooled then worked up with MTBE andwater. The organic phase is washed with water and brine then the solventis removed to afford compound 21.

Synthesis of1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid(compound 22)

Compound 21 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at80° C. overnight. The mixture is cooled to room temperature and ethanolis evaporated under vacuum. The residue is taken into water and MTBE, 1M HCl was added and the layers are separated. The MTBE layer was thentreated with dicyclohexylamine (0.97 equiv). The slurry is cooled to 0°C., filtered and washed with heptane to give the corresponding DCHAsalt. The salt is taken into MTBE and 10% citric acid and stirred untilall solids dissolve. The layers are separated and the MTBE layer waswashed with water and brine. Solvent swap to heptane followed byfiltration gives compound 22 after drying in a vacuum oven at 50° C.overnight.

Synthesis of 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonylchloride (compound 7)

Compound 22 (1.2 eq) is slurried in toluene (2.5 vol) and the mixtureheated to 60° C. SOCl₂ (1.4 eq) is added via addition funnel. Thetoluene and SOCl₂ are distilled from the reaction mixture after 30minutes. Additional toluene (2.5 vol) is added and distilled again.

Synthesis of ¹⁴C-(2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile(compound 23)

A solution of Compound 19 (1 eq) in DMSO (1.25 vol) is added to a slurryof Na¹⁴CN (1.4 eq) in DMSO (3 vol) maintaining the temperature between30-40° C. The mixture is stirred for 1 hour then water (6 vol) is addedfollowed by MTBE (4 vol). After stirring for 30 min, the layers areseparated. The aqueous layer is extracted with MTBE (1.8 vol). Thecombined organic layers are washed with water (1.8 vol), dried (Na₂SO₄),filtered, and concentrated to afford crude compound 23 that is purifiedby chromatography.

Synthesis of¹⁴C-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile(compound 24)

A mixture of compound 23 (1.0 eq) and 1,2-dibromoethane (1.8 eq) in THF(3 vol) is cooled to −10° C. via external chiller. 1 M LHMDS in THF (2.5eq) is added via an addition funnel and at a rate to maintain thetemperature in the reactor below 10° C. One hour after addition iscomplete, 20% w/v aq. citric acid (13 vol) is added via addition funnelmaintaining the temperature in the reactor below 20 C. The externalchiller is turned off and after stirring for 30 min the layers areseparated. The organic layer is filtered and concentrated to affordcrude compound 24 that is purified by chromatography.

Synthesis of¹⁴C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarboxylic acid(compound 25)

Compound 24 is hydrolyzed using 6 M NaOH (8 equiv) in ethanol (5 vol) at80° C. overnight. The mixture is cooled to room temperature and ethanolis evaporated under vacuum. The residue is taken into water and MTBE. 1M HCl is added to the mixture and the organic layer is filtered andconcentrated to afford compound 25.

Synthesis of¹⁴C-1-(2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonyl chloride(compound 26)

A mixture of Compound 25, 4-dimethylaminopyridine, and thionyl chloride(SOCl₂) in CH₂Cl₂ is stirred to produce compound 26, which may befurther reacted with compound 6 without isolation.

Amine Moiety Synthesis of tert-butyl-3-(3-methylpyridin-2-yl)benzoate(compound 4)

2-Bromo-3-methylpyridine (1.0 eq) is dissolved in toluene (12 vol).K₂CO₃ (4.8 eq) is added followed by water (3.5 vol) and the mixtureheated to 65° C. under a stream of N₂ for 1 hour.3-(t-Butoxycarbonyl)phenylboronic acid (1.05 eq) and Pd(dppf)Cl₂.CH₂Cl₂(0.015 eq) are then added and the mixture is heated to 80° C. After 2hours, the heat is turned off, water is added (3.5 vol) and the layersare allowed to separate. The organic phase is then washed with water(3.5 vol) and extracted with 10% aqueous methanesulfonic acid (2 eqMsOH, 7.7 vol). The aqueous phase is made basic with 50% aqueous NaOH (2eq) and extracted with EtOAc (8 vol). The organic layer is concentratedto afford crude compound 4 (82%) that is used directly in the next step.

Synthesis of 2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine-1-oxide(compound 5)

Compound 4 (1.0 eq) is dissolved in EtOAc (6 vol). Water (0.3 vol) isadded followed by urea-hydrogen peroxide (3 eq). The phthalic anhydride(3 eq) is added portion-wise as a solid to maintain the temperature inthe reactor below 45° C. After completion of phthalic anhydrideaddition, the mixture is heated to 45° C. After stirring for anadditional 4 hours, the heat is turned off. 10% w/w aqueous Na₂SO₃ (1.5eq) is added via addition funnel. After completion of Na₂SO₃ addition,the mixture is stirred for an additional 30 minutes and the layersseparated. The organic layer is stirred and 10% w/w aq. Na₂CO₃ (2 eq) isadded. After stirring for 30 minutes, the layers are allowed toseparate. The organic phase is washed 13% w/v aq NaCl. The organic phaseis then filtered and concentrated to afford crude compound 5 (95%) thatis used directly in the next step.

Synthesis of tert-butyl-3-(6-amino-3-methylpyridin-2-yl)benzoate(compound 6)

-   A solution of compound 5 (1 eq) and pyridine (4 eq) in MeCN (8 vol)    is heated to 70° C. A solution of methanesulfonic anhydride (1.5 eq)    in MeCN (2 vol) is added over 50 min via addition funnel maintaining    the temperature at less than 75° C. The mixture is stirred for an    additional 0.5 hours after complete addition. The mixture is then    allowed to cool to ambient. Ethanolamine (10 eq) is added via    addition funnel. After stirring for 2 hours, water (6 vol) is added    and the mixture is cooled to 10° C. After stirring for NLT 3 hours,    the solid is collected by filtration and washed with water (3 vol),    2:1 MeCN/water (3 vol), and MeCN (2×1.5 vol). The solid is dried to    constant weight (<1% difference) in a vacuum oven at 50° C. with a    slight N₂ bleed to afford compound 6 as a red-yellow solid (53%    yield).

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate(compound 8)

Compound 7 is dissolved in toluene (2.5 vol based on acid chloride) andadded via addition funnel to a mixture of compound 6 (1 eq),dimethylaminopyridine (DMAP, 0.02 eq), and triethylamine (3.0 eq) intoluene (4 vol based on compound 6). After 2 hours, water (4 vol basedon compound 6) is added to the reaction mixture. After stirring for 30minutes, the layers are separated. The organic phase is then filteredand concentrated to afford a thick oil of compound 8 (quantitative crudeyield). MeCN (3 vol based on crude product) is added and distilled untilcrystallization occurs. Water (2 vol based on crude product) is addedand the mixture stirred for 2 h. The solid is collected by filtration,washed with 1:1 (by volume) MeCN/water (2×1 vol based on crude product),and partially dried on the filter under vacuum.

The solid is dried to constant weight (<1% difference) in a vacuum ovenat 60° C. with a slight N₂ bleed to afford3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoateas a brown solid.

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid.HCL salt (compound 9).

To a slurry of compound 8 (1.0 eq) in MeCN (3.0 vol) is added water(0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixtureis heated to 45±5° C. After stirring for 24 to 48 hours the reaction iscomplete and the mixture is allowed to cool to ambient. Water (1.33 vol)is added and the mixture stirred. The solid is collected by filtration,washed with water (2×0.3 vol), and partially dried on the filter undervacuum. The solid is dried to constant weight (<1% difference) in avacuum oven at 60° C. with a slight N₂ bleed to afford compound 9 as anoff-white solid.

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid (Compound 1)

A slurry of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid.HCl (1 eq) in water (10 vol) is stirred at ambient temperature. Asample is taken after stirring for 24 hours. The sample is filtered andthe solid washed with water (2×). The solid sample is submitted for DSCanalysis. When DSC analysis indicates complete conversion to Compound 1,the solid is collected by filtration, washed with water (2×1.0 vol), andpartially dried on the filter under vacuum. The solid is dried toconstant weight (<1% difference) in a vacuum oven at 60° C. with aslight N₂ bleed to afford Compound 1 as an off-white solid (98% yield).

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid (Compound 1) using water and base

To a slurry of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid.HCl (1 eq) in water (10 vol) stirred at ambient temperature isadded 50% w/w aq. NaOH (2.5 eq). The mixture is stirred for NLT 15 minor until a homogeneous solution. Concentrated HCl (4 eq) is added tocrystallize Compound 1. The mixture is heated to 60° C. or 90° C. ifneeded to reduce the level of the t-butylbenzoate ester. The mixture isheated until HPLC analysis indicates NMT 0.8% (AUC) t-butylbenzoateester. The mixture is then cooled to ambient and the solid is collectedby filtration, washed with water (3×3.4 vol), and partially dried on thefilter under vacuum. The solid is dried to constant weight (<1%difference) in a vacuum oven at 60° C. with a slight N₂ bleed to affordCompound 1 as an off-white solid (97% yield).

Synthesis of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoicacid (Compound 1) directly from benzoate

A solution of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate(1.0 eq) in formic acid (3.0 vol) is heated to 70±10° C. The reaction iscontinued until the reaction is complete (NMT 1.0% AUC3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate)or heating for NMT 8 h. The mixture is allowed to cool to ambient. Thesolution is added to water (6 vol) heated at 50° C. and the mixturestirred. The mixture is then heated to 70±10° C. until the level of3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoateis NMT 0.8% (AUC). The solid is collected by filtration, washed withwater (2×3 vol), and partially dried on the filter under vacuum. Thesolid is dried to constant weight (<1% difference) in a vacuum oven at60° C. with a slight N₂ bleed to afford Compound 1 as an off-whitesolid.

An X-ray diffraction pattern calculated from a single crystal structureof Compound 1 in Form I is shown in FIG. 1. Table 1 lists the calculatedpeaks for FIG. 1.

TABLE 1 Peak 2θ Angle Relative Intensity Rank [degrees] [%] 11 14.4148.2 8 14.64 58.8 1 15.23 100.0 2 16.11 94.7 3 17.67 81.9 7 19.32 61.3 421.67 76.5 5 23.40 68.7 9 23.99 50.8 6 26.10 67.4 10 28.54 50.1

An actual X-ray powder diffraction pattern of Compound 1 in Form I isshown in FIG. 2. Table 2 lists the actual peaks for FIG. 2.

TABLE 2 Peak 2θ Angle Relative Intensity Rank [degrees] [%] 7 7.83 37.73 14.51 74.9 4 14.78 73.5 1 15.39 100.0 2 16.26 75.6 6 16.62 42.6 517.81 70.9 9 21.59 36.6 10 23.32 34.8 11 24.93 26.4 8 25.99 36.9

An overlay of an X-ray diffraction pattern calculated from a singlecrystal structure of Compound 1 in Form I, and an actual X-ray powderdiffraction pattern of Compound 1 in Form I is shown in FIG. 3. Theoverlay shows good agreement between the calculated and actual peakpositions, the difference being only about 0.15 degrees.

The DSC trace of Compound 1 in Form I is shown in FIG. 4. Melting forCompound 1 in Form I occurs at about 204° C.

Conformational pictures of Compound 1 in Form I based on single crystalX-ray analysis are shown in FIGS. 5-8. FIGS. 6-8 show hydrogen bondingbetween carboxylic acid groups of a dimer and the resulting stackingthat occurs in the crystal. The crystal structure reveals a densepacking of the molecules. Compound 1 in Form I is monoclinic, P2₁/n,with the following unit cell dimensions: a=4.9626(7) Å, b=12.299(2) Å,c=33.075 (4) Å, β=93.938(9)°, V=2014.0 Å³, Z=4. Density of Compound 1 inForm I calculated from structural data is 1.492 g/cm³ at 100 K.

¹HNMR spectra of Compound 1 are shown in FIGS. 9-11 (FIGS. 9 and 10depict Compound 1 in Form I in a 50 mg/mL, 0.5 methylcellulose-polysorbate 80 suspension, and FIG. 11 depicts Compound 1 asan HCl salt).

Table 3 below recites additional analytical data for Compound 1.

TABLE 3 Cmpd. LC/MS LC/RT No. M + 1 min NMR 1 453.3 1.93 H NMR (400 MHz,DMSO-d6) 9.14 (s, 1H), 7.99-7.93 (m, 3H), 7.80-7.78 (m, 1H), 7.74-7.72(m, 1H), 7.60-7.55 (m, 2H), 7.41-7.33 (m, 2H), 2.24 (s, 3H), 1.53-1.51(m, 2H), 1.19-1.17 (m, 2H)

1-35. (canceled)
 36. A process for preparing a compound of formula I:

comprising the step of: ia) reacting a compound of formula 6a:

wherein, R is H, C₁₋₆ aliphatic, aryl, aralkyl, heteroaryl, cycloalkyl, or heterocycloalkyl; R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂, halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂, —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂, —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂, —COCOR^(J); R^(J) is hydrogen or C₁₋₆ aliphatic; o is an integer from 0 to 3 inclusive; and p is an integer from 0 to 5 inclusive; with a compound of formula 7a:

wherein, A is a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring; R₁ is independently selected from —R^(J), —OR^(J), —N(R^(J))₂, —NO₂, halogen, —CN, —C₁₋₄haloalkyl, —C₁₋₄haloalkoxy, —C(O)N(R^(J))₂, —NR^(J)C(O)R^(J), —SOR^(J), —SO₂R^(J), —SO₂N(R^(J))₂, —NR^(J)SO₂R^(J), —COR^(J), —CO₂R^(J), —NR^(J)SO₂N(R^(J))₂, —COCOR^(J); R^(J) is hydrogen or C₁₋₆ aliphatic; m is an integer from 0 to 3 inclusive; n is an integer from 1 to 4 inclusive; and X is a halo or OH; in a second organic solvent in the presence of a second base.
 37. The process of claim 36, wherein the second organic solvent is an aprotic solvent.
 38. The process of claim 36, wherein the second organic solvent is toluene.
 39. The process of claim 36, wherein the second base is an organic base.
 40. The process of claim 36, wherein the second base is triethylamine.
 41. The process of claim 36, wherein the reaction between compound 6a and compound 7a is carried out in the presence of a catalytic amine.
 42. The process of claim 36, wherein the reaction between compound 6a and compound 7a is carried out in the presence of a catalytic amount of dimethylaminopyridine.
 43. The process of claim 36, wherein when R₁ on the phenyl ring in formula I is an ester, the process further comprises de-esterifying the compound of formula I in a biphasic mixture comprising water, a third organic solvent, and a first acid to give an acid salt.
 44. The process of claim 43, wherein the third organic solvent is acetonitrile.
 45. The process of claim 43, the first acid is an inorganic acid.
 46. The process of claim 43, wherein the first acid is hydrochloric acid.
 47. The process of claim 43, wherein the de-esterification reaction is run at between 20° C. and 60° C.
 48. The process of claim 43, wherein the acid salt is converted to the free form, Form I, by slurrying or dissolving the acid salt in an appropriate solvent for an effective amount of time.
 49. The process of claim 48, wherein the appropriate solvent is selected from water or a 50% methanol/water mixture.
 50. The process of claim 48, wherein the appropriate solvent is water.
 51. The process of claim 48, wherein the effective amount of time is between 2 and 24 hours.
 52. The process of claim 48, further comprising the step of filtering the slurry of the compound of formula I in Form I, or concentrating the solution of the compound of formula I in Form I to effect recrystallization and filtering the recrystallized compound of formula I in Form I. 53-103. (canceled) 